Single Gene Deletions of Orexin, Leptin, Neuropeptide Y, and Ghrelin Do Not Appreciably Alter Food Anticipatory Activity in Mice

Timing activity to match resource availability is a widely conserved ability in nature. Scheduled feeding of a limited amount of food induces increased activity prior to feeding time in animals as diverse as fish and rodents. Typically, food anticipatory activity (FAA) involves temporally restricting unlimited food access (RF) to several hours in the middle of the light cycle, which is a time of day when rodents are not normally active. We compared this model to calorie restriction (CR), giving the mice 60% of their normal daily calorie intake at the same time each day. Measurement of body temperature and home cage behaviors suggests that the RF and CR models are very similar but CR has the advantage of a clearly defined food intake and more stable mean body temperature. Using the CR model, we then attempted to verify the published result that orexin deletion diminishes food anticipatory activity (FAA) but observed little to no diminution in the response to CR and, surprisingly, that orexin KO mice are refractory to body weight loss on a CR diet. Next we tested the orexigenic neuropeptide Y (NPY) and ghrelin and the anorexigenic hormone, leptin, using mouse mutants. NPY deletion did not alter the behavior or physiological response to CR. Leptin deletion impaired FAA in terms of some activity measures, such as walking and rearing, but did not substantially diminish hanging behavior preceding feeding time, suggesting that leptin knockout mice do anticipate daily meal time but do not manifest the full spectrum of activities that typify FAA. Ghrelin knockout mice do not have impaired FAA on a CR diet. Collectively, these results suggest that the individual hormones and neuropepetides tested do not regulate FAA by acting individually but this does not rule out the possibility of their concerted action in mediating FAA

Liverpool Telescope 2: beginning the design phase

The Liverpool Telescope is a fully robotic 2-metre telescope located at the Observatorio del Roque de los Muchachos on the Canary Island of La Palma. The telescope began routine science operations in 2004, and currently seven simultaneously mounted instruments support a broad science programme, with a focus on transient followup and other time domain topics well suited to the characteristics of robotic observing. Work has begun on a successor facility with the working title ‘Liverpool Telescope 2’. We are entering a new era of time domain astronomy with new discovery facilities across the electromagnetic spectrum, and the next generation of optical survey facilities such as LSST are set to revolutionise the field of transient science in particular. The fully robotic Liverpool Telescope 2 will have a 4-metre aperture and an improved response time, and will be designed to meet the challenges of this new era. Following a conceptual design phase, we are about to begin the detailed design which will lead towards the start of construction in 2018, for first light ∼2022. In this paper we provide an overview of the facility and an update on progress. © (2016) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only

Alcohol affects neuronal substrates of response inhibition but not of perceptual processing of stimuli signalling a stop response

Alcohol impairs inhibitory control, including the ability to terminate an initiated action. While there is increasing knowledge about neural mechanisms involved in response inhibition, the level at which alcohol impairs such mechanisms remains poorly understood. Thirty-nine healthy social drinkers received either 0.4g/kg or 0.8g/kg of alcohol, or placebo, and performed two variants of a Visual Stop-signal task during acquisition of functional magnetic resonance imaging (fMRI) data. The two task variants differed only in their instructions: in the classic variant (VSST), participants inhibited their response to a “Go-stimulus” when it was followed by a “Stop-stimulus”. In the control variant (VSST_C), participants responded to the “Go-stimulus” even if it was followed by a “Stop-stimulus”. Comparison of successful Stop-trials (Sstop)>Go, and unsuccessful Stop-trials (Ustop)>Sstop between the three beverage groups enabled the identification of alcohol effects on functional neural circuits supporting inhibitory behaviour and error processing. Alcohol impaired inhibitory control as measured by the Stop-signal reaction time, but did not affect other aspects of VSST performance, nor performance on the VSST_C. The low alcohol dose evoked changes in neural activity within prefrontal, temporal, occipital and motor cortices. The high alcohol dose evoked changes in activity in areas affected by the low dose but importantly induced changes in activity within subcortical centres including the globus pallidus and thalamus. Alcohol did not affect neural correlates of perceptual processing of infrequent cues, as revealed by conjunction analyses of VSST and VSST_C tasks. Alcohol ingestion compromises the inhibitory control of action by modulating cortical regions supporting attentional, sensorimotor and action-planning processes. At higher doses the impact of alcohol also extends to affect subcortical nodes of fronto-basal ganglia- thalamo-cortical motor circuits. In contrast, alcohol appears to have little impact on the early visual processing of infrequent perceptual cues. These observations clarify clinically-important effects of alcohol on behaviour

Eating Behaviour And Neural Representations Of Hunger And Satiety In Patients With Acquired Structural Hypothalamic Damage: A Clinical And Functional Neuroimaging Study

Hypothalamic obesity (HO) is a relatively rare cause of obesity within the population as a whole, but studies of patients with hypothalamic damage show there is a significant prevalence of obesity within the patient group. Additionally, the obesity is difficult to prevent and manage and increases morbidity and mortality in an already at risk patient group. The work of this thesis had two main objectives. Firstly, to examine the prevalence of obesity and associated morbidities in patients with acquired, structural hypothalamic damage with a descriptive cohort study (n=110). A separate descriptive study quantified obesity and metabolic risk factors in young patients with pituitary tumours, with or without hypothalamic damage (n=41), as they were also identified as a possible at risk group during clinical observations. The second objective was to investigate the underlying pathophysiology of HO using various complementary techniques to study patients with hypothalamic damage who remained weight-stable (HWS), patients with HO and age- and BMI-matched controls. These cross-sectional case-control studies used functional magnetic resonance imaging (fMRI; 9 HO, 7 HWS, 20 controls), the universal eating monitor (UEM; 6 HO, 6 HWS, 9 obese controls [OC], 10 non-obese controls [NOC]), Three-Factor Eating Questionnaire (TFEQ; 8 HO, 6 HWS, 9 OC, 11 NOC) and three-day food diaries (6 HO, 7 HWS, 8 OC, 11 NOC) to assess eating behaviour. The first descriptive study included 110 adults with tumours causing hypothalamic damage attending a specialist neuroendocrine clinic. There was a significant prevalence of weight gain and obesity; 81.8% were overweight/heavier, 56.4% obese and 13.6% morbidly obese, despite proactive assessment and treatment during routine clinic visits. Hypertension (30.9%), dyslipidaemia (54.5%), type 2 diabetes mellitus (T2DM) (14.5%) and cardiovascular disease (9.1%) were also prevalent. In 41 patients with childhood/adolescent-onset pituitary adenomas there was also a relatively high prevalence of obesity (39.0%) and cardiovascular risk factors (2 receiving antihypertensive medications, 2 with T2DM and 4 with treated dyslipidaemia), despite the majority of tumours being microadenomas (i.e. too small to cause hypothalamic damage and indicating the need for long-term follow-up of these patients. The first study into the pathophysiology of HO involved the use of functional MRI in 9 patients with HO, 7 HWS and 20 age- and BMI-matched controls. Participants underwent fMRI scans in a fasted state, as well as one hour and three hours following a fixed-load breakfast (25% of their calculated basal metabolic rate [BMR]). At each scan session participants viewed alternating blocks of photographs of high- or low-calorie food, with non-food photographs also viewed to use as a baseline comparison, to allow purely visual activation to be subtracted from any BOLD signal differences which occurred. Whole-brain statistical analysis revealed significantly lower BOLD signal in HWS participants compared to HO (and to controls) in the food motivation and reward-related brain regions of the posterior insula and lingual gyrus (p=0.001) when viewing high-calorie food photographs (compared to non-food photographs). These differences in reward-related brain regions may be implicated in the development of HO/the ability to remain weight-stable despite hypothalamic damage. Eating behaviour studies were undertaken on a separate study day where participants were asked to eat an unlimited pasta meal until adequately full, while seated at the UEM. This allowed monitoring of total intake, eating duration, eating rate and intra-meal on-screen ratings of hunger, fullness and meal pleasantness using visual analogue scales. Additionally Three Factor Eating Questionnaires (TFEQs) and three-day MRC-Human Nutrition Research diaries were completed at home to assess more long-term real-world eating habits. None of the eating behaviour studies identified significant statistical differences between HO and HWS, but this may have been due to lack of statistical power. There was however an unusual pattern of eating rate in those with HO on visual ascription. This involved an initial tendency towards a higher eating rate, followed by a reduction in rate, with a further increase towards the end of the meal. Further investigation of this pattern with larger numbers of participants would be important to determine whether it is a significant finding or merely an anomaly due to the small group size. Interestingly controls ate significantly more at the UEM (even when intake was adjusted according to fat-free mass or as a proportion of the estimated BMR) and for significantly longer than participants with hypothalamic damage, who reported lower hunger at the start of the meal, but there was no difference between obese and non-obese participants. In keeping with previously published research disinhibition scores measured using the TFEQ were higher in participants with simple obesity [1], with no evidence of increased disinhibition in HO participants [2], although the small numbers studied should be noted. Finally, during both of the study days blood sampling was undertaken to look for biochemical/hormonal variances between the groups. Fasting and area under the curve (AUC) active ghrelin concentrations were significantly higher in controls than in patients, in keeping with some (but not all) previous studies [2-4]. Consistent with previously published research leptin concentrations were significantly higher in obese compared to non-obese participants The small size of this study was a significant limitation and limits the generalisability of the findings, particularly in the eating behaviour studies. This was due in part to the rarity of the condition - the occurrence of acquired, structural hypothalamic damage is relatively rare and the number of individuals with hypothalamic damage who remain weight stable is small, leading to particular difficulty in recruiting patients for the HWS group. Whilst there were some interesting findings further larger studies should enable greater clarification and would allow correlation between clinical and biochemical findings. Further studies in larger cohorts could explore the unusual eating pattern seen in those with HO when studied using the UEM and the apparent lack of disinhibition seen in this group. Although this research provides some preliminary novel evidence to support differences in BOLD signal in reward-related regions of the brain as a possible driver of HO, the mechanisms through which these differences exert their effects to contribute to the development of HO require further elucidation and further study with larger numbers of patients is needed

Liverpool Telescope follow-up of candidate electromagnetic counterparts during the first run of Advanced LIGO

The first direct detection of gravitational waves was made in late 2015 with the Advanced LIGO detectors. By prior arrangement, a worldwide collaboration of electromagnetic follow-up observers were notified of candidate gravitational wave events during the first science run, and many facilities were engaged in the search for counterparts. No counterparts were identified, which is in line with expectations given that the events were classified as black hole - black hole mergers. However these searches laid the foundation for similar follow-up campaigns in future gravitational wave detector science runs, in which the detection of neutron star merger events with observable electromagnetic counterparts is much more likely. Three alerts were issued to the electromagnetic collaboration over the course of the first science run, which lasted from September 2015 to January 2016. Two of these alerts were associated with the gravitational wave events since named GW150914 and GW151226. In this paper we provide an overview of the Liverpool Telescope contribution to the follow-up campaign over this period. Given the hundreds of square degree uncertainty in the sky position of any gravitational wave event, efficient searching for candidate counterparts required survey telescopes with large (~degrees) fields-of-view. The role of the Liverpool Telescope was to provide follow-up classification spectroscopy of any candidates. We followed candidates associated with all three alerts, observing 1, 9 and 17 candidates respectively. We classify the majority of the transients we observed as supernovae

Neural correlates of sexual cue reactivity in individuals with and without compulsive sexual behaviours

Although compulsive sexual behaviour (CSB) has been conceptualized as a "behavioural" addiction and common or overlapping neural circuits may govern the processing of natural and drug rewards, little is known regarding the responses to sexually explicit materials in individuals with and without CSB. Here, the processing of cues of varying sexual content was assessed in individuals with and without CSB, focusing on neural regions identified in prior studies of drug-cue reactivity. 19 CSB subjects and 19 healthy volunteers were assessed using functional MRI comparing sexually explicit videos with non-sexual exciting videos. Ratings of sexual desire and liking were obtained. Relative to healthy volunteers, CSB subjects had greater desire but similar liking scores in response to the sexually explicit videos. Exposure to sexually explicit cues in CSB compared to non-CSB subjects was associated with activation of the dorsal anterior cingulate, ventral striatum and amygdala. Functional connectivity of the dorsal anterior cingulate-ventral striatum-amygdala network was associated with subjective sexual desire (but not liking) to a greater degree in CSB relative to non-CSB subjects. The dissociation between desire or wanting and liking is consistent with theories of incentive motivation underlying CSB as in drug addictions. Neural differences in the processing of sexual-cue reactivity were identified in CSB subjects in regions previously implicated in drug-cue reactivity studies. The greater engagement of corticostriatal limbic circuitry in CSB following exposure to sexual cues suggests neural mechanisms underlying CSB and potential biological targets for interventions

Numerical simulation of blood flow and pressure drop in the pulmonary arterial and venous circulation

A novel multiscale mathematical and computational model of the pulmonary circulation is presented and used to analyse both arterial and venous pressure and flow. This work is a major advance over previous studies by Olufsen et al. (Ann Biomed Eng 28:1281–1299, 2012) which only considered the arterial circulation. For the first three generations of vessels within the pulmonary circulation, geometry is specified from patient-specific measurements obtained using magnetic resonance imaging (MRI). Blood flow and pressure in the larger arteries and veins are predicted using a nonlinear, cross-sectional-area-averaged system of equations for a Newtonian fluid in an elastic tube. Inflow into the main pulmonary artery is obtained from MRI measurements, while pressure entering the left atrium from the main pulmonary vein is kept constant at the normal mean value of 2 mmHg. Each terminal vessel in the network of ‘large’ arteries is connected to its corresponding terminal vein via a network of vessels representing the vascular bed of smaller arteries and veins. We develop and implement an algorithm to calculate the admittance of each vascular bed, using bifurcating structured trees and recursion. The structured-tree models take into account the geometry and material properties of the ‘smaller’ arteries and veins of radii ≥ 50 μ m. We study the effects on flow and pressure associated with three classes of pulmonary hypertension expressed via stiffening of larger and smaller vessels, and vascular rarefaction. The results of simulating these pathological conditions are in agreement with clinical observations, showing that the model has potential for assisting with diagnosis and treatment for circulatory diseases within the lung